Development of Human Membrane Transporters: …...patterns of membrane transporters in animals are...

REVIEW ARTICLE

Development of Human Membrane Transporters: DrugDisposition and Pharmacogenetics

Miriam G. Mooij1 • Anne T. Nies2,3 • Catherijne A. J. Knibbe4,5 • Elke Schaeffeler2,3 •

Dick Tibboel1 • Matthias Schwab2,6 • Saskia N. de Wildt1

Published online: 26 September 2015

� The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract Membrane transporters play an essential role in

the transport of endogenous and exogenous compounds,

and consequently they mediate the uptake, distribution, and

excretion of many drugs. The clinical relevance of trans-

porters in drug disposition and their effect in adults have

been shown in drug–drug interaction and pharmacoge-

nomic studies. Little is known, however, about the onto-

geny of human membrane transporters and their roles in

pediatric pharmacotherapy. As they are involved in the

transport of endogenous substrates, growth and develop-

ment may be important determinants of their expression

and activity. This review presents an overview of our

current knowledge on human membrane transporters in

pediatric drug disposition and effect. Existing pharma-

cokinetic and pharmacogenetic data on membrane sub-

strate drugs frequently used in children are presented and

related, where possible, to existing ex vivo data, providing

a basis for developmental patterns for individual human

membrane transporters. As data for individual transporters

are currently still scarce, there is a striking information gap

regarding the role of human membrane transporters in drug

therapy in children.

Key Points

Little is known about the ontogeny of transporters

and their roles in pediatric pharmacotherapy.

Ex vivo, pharmacokinetic and pharmacogenetic

studies suggest transporter-specific changes from the

human fetus to the adult.

No clear transporter-specific maturation pattern can

be deducted at this time, hence, further research is

needed.Electronic supplementary material The online version of thisarticle (doi:10.1007/s40262-015-0328-5) contains supplementarymaterial, which is available to authorized users.

& Saskia N. de Wildt

[email protected]

Miriam G. Mooij

[email protected]

Anne T. Nies

[email protected]

Catherijne A. J. Knibbe

[email protected]

Elke Schaeffeler

[email protected]

Dick Tibboel

[email protected]

Matthias Schwab

[email protected]

1 Intensive Care and Department of Pediatric Surgery, Erasmus

MC-Sophia Children’s Hospital, Room Sp-3458,

Wytemaweg 80, PO-box 2060, 3000 CB Rotterdam,

The Netherlands

2 Dr. Margarete Fischer-Bosch Institute of Clinical

Pharmacology, Stuttgart, Germany

3 University of Tuebingen, Tuebingen, Germany

4 Faculty of Science, Leiden Academic Centre for Research,

Pharmacology, Leiden, The Netherlands

5 Hospital Pharmacy and Clinical Pharmacology, St. Antonius

Hospital, Nieuwegein, The Netherlands

6 Department of Clinical Pharmacology, University Hospital

Tuebingen, Tuebingen, Germany

Clin Pharmacokinet (2016) 55:507–524

DOI 10.1007/s40262-015-0328-5

http://dx.doi.org/10.1007/s40262-015-0328-5

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http://crossmark.crossref.org/dialog/?doi=10.1007/s40262-015-0328-5&domain=pdf

1 Introduction

Plasma membrane transporters play an essential role in the

uptake of endogenous compounds into cells and their efflux

from cells. They also mediate the absorption, distribution,

and excretion of a large number of drugs [1, 2]. In par-

ticular, two major transporter superfamilies are the focus of

pharmacological studies: the adenosine triphosphate

(ATP)-binding cassette (ABC) transporters and the solute

carrier (SLC) transporter superfamilies [3, 4]. The

nomenclature is presented in Table 1. Numerous studies,

mostly in adults, have investigated altered membrane

transporter functions due to genetic variants or drug–drug

interactions by co-medications [1, 5–9]. Studies on the role

of membrane transporters in children are scarce, however.

Still, growth and maturation are likely to have an impact on

activity of these transporters in light of their role in

endogenous processes. Animal studies have indeed shown

developmental changes in membrane transporter expres-

sion [10]. The aim of this review is to present an up-to-date

overview on our current knowledge on the role of human

membrane transporters in pediatric drug disposition and

effect. For this purpose, a short overview of ex vivo studies

is presented after which results from pharmacokinetic and

pharmacogenetic studies of relevant membrane transporters

are reported that may broaden our insight into develop-

mental patterns for individual human membrane

transporters.

2 Ex Vivo Studies on the Ontogeny of HumanMembrane Transporters

Ex vivo data from pediatric samples may be used to

extrapolate existing adult pharmacokinetic data to children,

as is done using physiologically based pharmacokinetic

(PBPK) modeling [11, 12]. Expression patterns of mem-

brane transporters during human development have been

studied in postmortem and surgical tissue samples with the

use of different techniques such as immunohistochemistry

Table 1 Nomenclature of human membrane transporters: selection transporters discussed in this paper [source: NCBI Gene (http://www.ncbi.

nlm.nih.gov/gene)]

Gene Protein

Name Locus Name Synonyms

ABC transporters

ABCB1 7q21.12 ABCB1 MDR1, P-glycoprotein (P-gp), CLCS, PGY1, ABC20, CD243, GP170

ABCC2 10q24 ABCC2 MRP2, CMOAT, DJS, cMRP, ABC30

ABCC3 17q22 ABCC3 MRP3, MOAT-D, cMOAT2, MLP2, ABC31, EST90757

ABCC4 13q32 ABCC4 MRP4, MOAT-B, MOATB

ABCG2 4q22 ABCG2 BRCP, MXR, MRX, ABCP, BMDP, MXR1, BCRP1, CD338, GOUT1,

CDw338, UAQTL1, EST157481

SLC transporters

SLCO1B1 12p OATP1B1 OATP2, LST-1, OATP-C, HBLRR, LST1, SLC21A6

SLCO1B3 12p12 OATP1B3 OATP8, LST-2, LST3, HBLRR, SLC21A8, LST-3TM13

SLCO2B1 11q13 OATP2B1 OATP-B, SLC21A9

SLC3A2 11q13 4F2hc 4F2, CD98, MDU1, 4T2HC, NACAE, CD98HC

SLC22A1 6q25.3 OCT1 HOCT1, oct1_cds

SLC22A2 6q25.3 OCT2

SLC22A6 11q12.3 OAT1 PAHT, HOAT1, ROAT1

SLC22A7 6q21.1 OAT2 NLT

SLC22A8 11q11 OAT3

SLC15A1 13q32.3 PEPT1 HPEPT1, HPECT1

SLC47A1 17q11.2 MATE1

SLC47A2 17q11.2 MATE2-K MATE2, MATE2-B

Other

FAAH 1p35-p34 FAAH FAAH-1, PSAB

ADRB2 5q31-q32 ADRB2 BAR, B2AR, ADRBR, ADRB2R, BETA2AR

CDH17 8q22.1 HPT1 CDH16, LI cadherin

ABC adenosine triphosphate (ATP)-binding cassette, ADRB2 b2-adrenergic receptor, FAAH fatty acid hydrolase, SLC solute carrier

508 M. G. Mooij et al.

http://www.ncbi.nlm.nih.gov/gene

http://www.ncbi.nlm.nih.gov/gene

to visualize tissue localization, reverse transcriptase poly-

merase chain reaction (RT-PCR) for messenger RNA

(mRNA) expression, Western blotting and new liquid

chromatography–tandem mass spectrometry (LC–MS/MS)

techniques to quantify transporter protein abundance. To

the best of our knowledge, transporter activity studies using

human pediatric tissue are non-existent. Although animal

data may provide valuable insight, potential developmental

patterns of membrane transporters in animals are likely to

differ from those in humans, as studies on drug metabo-

lizing enzymes (DMEs) have shown [13–15]. Moreover,

animal studies do not provide any information when there

are no direct orthologs in rodents, as is the case, for

example, for human organic anion-transporting polypep-

tide (OATP) 1B1 and OATP1B3.

From the embryonic and fetal period, most transporter

data result from immunohistochemistry and mRNA

expression studies. These data, often covering a small age

range and/or small sample size, suggest transporter-specific

maturation with a low fetal/neonatal or stable expression

pattern, but quantification is lacking [16–19]. The ex vivo

data from the first years of life consist mainly of hepatic

and intestinal mRNA expression data, with the inherent

limitation of a possible lack of correlation with protein

expression [20–24]. In children from 7 years onwards,

protein abundance data generated using LC–MS/MS have

been recently published [25–27]. Although a large pediatric

age range was covered by this project, the younger age

range, where most developmental changes are expected, is

lacking in protein abundance data.

The studies referenced above comprise the most sig-

nificant studies investigating the maturation of human

membrane transporters, with an emphasis on the clinically

relevant transporters ABCB1, ABCC2, OATP1B1, and

OATP1B3. The best-studied transporter during human

development is ABCB1 (Fig. 1). Interestingly, its devel-

opmental pattern seems organ-specific. In fetal intestinal

samples (16th to 20th week of gestation), ABCB1 could be

visualized [16] and intestinal mRNA data suggests

stable ABCB1 expression from the neonate up to the adult

[22, 24]. In the liver, mRNA expression data suggest a

pattern of low ABCB1 expression in fetuses, neonates, and

infants until 12 months of age, after which it increases to

adult levels [21, 22]. ABCB1 protein abundance measured

using LC–MS/MS was quite variable (4.8-fold) in 64

subjects in the age range 7–70 years, but this variation

could not be explained by either age or sex [25]. In fetal

human brain samples ranging from 7 to 28 weeks of ges-

tational age, ABCB1 immunostaining was detected in only

one sample from a 28-week fetus [16]. In contrast, in

postmortem central nervous system tissue from neonates

(n = 28) of 22–42 weeks of gestational age and from

adults (n = 3), immunohistochemistry showed increasing

ABCB1 staining with gestational age [28]. ABCB1 gene

expression was also detected in the brain of fetuses of 15,

27, and 42 weeks of gestational age [18]. Very recently, the

ABCB1 protein was shown to be limited at birth and to

increase postnatally to reach adult levels by 3–6 months of

age [29]. Renal ABCB1 mRNA expression appears to be

related to maturity of nephrons. A trend towards lower

expression in fetuses and neonates than in adults was

observed. ABCB1 protein has been identified as early as

the 5.5th week of gestation [16, 17, 21].

Fig. 1 Suggested ontogeny of

ABCB1 expression in intestine,

liver, kidney, and brain. ABC

adenosine triphosphate (ATP)-

binding cassette

Ontogeny and Pharmacogenetics of Human Membrane Transporters 509

ABCC2 ontogeny shows similarities to ABCB1. Small

intestine ABCC2 mRNA expression is stable in neonatal

surgical patients compared to adults. While, hepatic

ABCC2 mRNA expression is much lower in the fetus,

neonate, and young infant (up to 200-fold lower) than the

adult [22, 27], in children from 7 years onwards its protein

expression appears stable [27]. On the protein level, both

the localization pattern and intensity of ABCC2 protein

staining appear to change during fetal life, in concert with

fetal liver maturation [19, 23].

Hepatic mRNA expression of OATP1B1 and OATP1B3

appears to show a different developmental pattern than

ABCB1 and ABCC2. Although fetal expression was 2- to

30-fold lower than adult expression, neonatal and infant

expression appeared to be even lower (up to 600-fold) [19,

22]. This pattern appears to be supported by protein data

(Western blotting) for OATP1B3 but not for OATP1B1. In

one study, OATP1B1 protein expression already appears at

adult levels in neonates, while in another OATP1B1 only

increases after the age of 6 years [30, 31]. Again, for both

OATP1B1 and OATP1B3, protein expression appears

stable at adult levels from 7 years onwards [25].

3 Pharmacokinetic and Pharmacogenetic Studiesof Relevant Membrane Transporter Substrates

Pharmacokinetic and pharmacogenetic studies may provide

insight into the impact of selected drug transporters in vivo.

We identified 16 drugs frequently prescribed to children

and that are known substrates of one or more specific

membrane transporters (Table 2; see the Electronic Sup-

plementary Material for the search strategy). Age-related

differences in pharmacokinetic or pharmacogenetic studies

may point to maturational changes in the transporter

involved. On the other hand, concordance between adult

and pediatric pharmacogenomic studies may support the

presence and potentially similar expression of the involved

transporters in children as in adults. To further support a

potential developmental pattern, we compared the in vivo

data with relevant ex vivo data of the individual trans-

porters. As many drugs are also substrates of DMEs and/or

multiple transporters, the presented data must be inter-

preted in the context of the interplay with metabolizing

enzymes. It can be speculated that when a specific DME is

developmentally low at a certain age, while the transporter

is already mature, this may impact the disposition of a drug

by potentially altering the absorption, distribution, meta-

bolism, and excretion (ADME) pathway from largely DME

based to transporter based. Where possible, we have only

included data that are highly supportive of a role for the

transporter(s) involved. Table 2 provides a summary of the

pharmacokinetic studies in children and the relationship

with transporters. For detailed genetic information on

individual transporters, the reader is referred to The Phar-

macogenomics Knowledgebase (www.pharmgkb.org) and

recent reviews [7, 8, 32–34].

3.1 Digoxin-ABCB1

The cardiac glycoside digoxin is a well-known ABCB1

substrate (Fig. 2). Its US Food and Drug Administration

(FDA) drug label warns about pharmacokinetic interactions

with intestinal or renal ABCB1 inducers or inhibitors.

Digoxin is mainly renally cleared as unchanged drug: 80 %

by glomerular filtration and 20 % by tubular secretion [35].

Pharmacokinetic studies in children show clear age-related

differences. In a population pharmacokinetic analysis in 71

neonates (age range 2–29 days), oral digoxin clearance

increased non-linearly with increasing bodyweight and

gestational age [36]. The estimated clearance of digoxin in

a term-born 3 kg newborn is 0.338 L/kg/h at a serum

concentration of 1 ng/mL. A population pharmacokinetic

study in older infants [n = 117, mean age (range) 0.76

(0.08–4.43) years] also found increased oral digoxin

clearance with increasing bodyweight [37]. In this study,

the simulated apparent oral clearance (CL/F) of an 8 kg

infant was 0.43 L/h/kg at a target concentration of 1 ng/

mL. Interestingly, digoxin clearance normalized for body-

weight appears to be much higher in term neonates and

younger children than in adults (0.17 L/h/kg). This obser-

vation is also in line with higher (per kg) dosing recom-

mendations in term neonates and infants. However, as the

drug is mainly renally cleared, and glomerular filtration is

still immature at birth, one would expect a lower body size-

corrected clearance. This was indeed the case in preterm

infants (\2.5 kg) whose digoxin bodyweight-corrected

clearance was much lower than that of term infants (0.064

vs. 0.1 L/h/kg), in line with lower dosing recommendations

for this age group [38]. Thus, in preterm newborns, both

the glomerular filtration rate (GFR) and ABCB1 may be

immature at birth, while in term infants ABCB1 activity

may already be more mature and compensate for devel-

opmentally low GFR.

Additionally, clearance decreases non-linearly with

increasing concentrations in the range of 0.2 and 2 ng/mL

in children up to 4.5 years of age, whereas non-linearity in

adults is only found from a serum concentration of 7 ng/

mL onwards. We can only speculate as to the underlying

mechanism. Earlier transporter saturation due to immature

ABCB1 activity in intestine and kidney contradicts the

observation of higher bodyweight-corrected clearance in

young children than in adults.

A clinically relevant interaction was found in eight

children who were co-administered the ABCB1 inhibitor

carvedilol. Digoxin clearance decreased twofold, while the


http://www.pharmgkb.org

Table 2 Summary pharmacokinetic and pharmacogenetic studies of relevant membrane transporter substrates

Drug Relevant transporters involved

in transport of drug

PK and PGx results in children

Digoxin ABCB1 Higher bodyweight-corrected digoxin clearance in term neonates and young children

[36–38]. Renal clearance of digoxin in young children may be more dependent on

ABCB1-mediated tubular secretion than in adults [39]

Tacrolimus ABCB1 PGx studies of ABCB1 in relation to tacrolimus PKs appear contradictory [42, 43, 46,

47]. In pediatric liver transplant recipients, high intestinal ABCB1 mRNA

expression was associated with a twofold higher tacrolimus clearance [48]

Daptomycin ABCB1 Higher body size-corrected renal daptomycin clearance in neonates and younger

infants [51–53]

Fexofenadine OATP2B1, ABCB1, MRP2 Apparent bodyweight-corrected oral clearance was 1.5-fold lower in children

6 months to 6 years than in children 6–12 years [58]

Morphine OCT1, ABCB1, ABCC2,

ABCC3, OATP1B1

Neonates and infants have low morphine clearance in the first 10 days of life,

increasing thereafter, largely due to immature UGT2B7 metabolism, but

transporters may contribute [64, 65]. Neonates are more prone to morphine-related

respiratory depression [66]. ABCB1 genotype was associated with respiratory

depression in older children, in contrast to an adult study [62]. Also, ABCB1

genotype affects the M3G-formation and OCT1 genotype is associated with

variation in morphine clearance and glucuronide-metabolites formation [68]

Pravastatin OATP1B1, OATP2B1,

OATP1B3, ABCB1, ABCC2

Children with hypercholesterolemia and the SLCO1B1 –11187GA variant had lower

mean pravastatin AUCs than those with the wild-type, in contrast to an adult study

where the opposite effect was found [71, 72]. No age-related variability in

pravastatin PKs from children aged 5 years onwards [73]

Atorvastatin OATP1B1, BCRP Atorvastatin PKs in older children similar to adult PKs [74]

Bosentan OATP1B1, OATP1B3,

OATP2B1

In children, an exposure limit was found at a much lower dose than in adults, which

might be due to intestinal OATP2B1 saturation [80]

Ondansetron OCT1 Ondansetron PKs and clinical efficacy have been correlated with OCT1 genotypes in

adults [82]. Ondansetron clearance increased with age in children aged

1–48 months [83]

Metformin OCT, MATE1, MATE2 K Metformin PKs in children from 9 years of age onwards were comparable with adult

PKs, suggesting stable OCT and MATE activity [91]

Cimetidine OCT2, MATE1, MATE2 K,

OAT2

In neonates and children, cimetidine (and metabolites) renal clearance accounts for

80–90 % of total clearance, whereas in adults it accounts for 60 % of total

clearance [93–95]. The relatively high renal clearance suggests mature OCT2

activity at birth in the presence of immature GFR [99]

Tramadol OCT1 In adults, OCT1 genotype was related to metabolite plasma concentrations and

prolonged miosis [101]. Tramadol and metabolite PKs show age-related changes in

neonates [102]

Methotrexate OATP1B1, ABCC2 Increased renal toxicity in children 0–3 months old compared with infants

7–12 months [106]. From 1 year of age onwards, body size-corrected methotrexate

clearance decreased linearly with age [107]. SLCO1B1 genotype was associated

with increased AUC and was a predictor for toxicity [107]

Mycophenolate

mofetil

MRP2 In pediatric patients, ABCC2 rs717620 allele has been associated with reduced

exposure to MPA, more adverse effects, and rejection [114]

Acyclovir/valacyclovir 4F2hc, HPT1, OAT1, OAT3 In neonates, the IV acyclovir bodyweight-corrected clearance showed a twofold

increase from 25 to 41 weeks of gestational age [118]. In older children, 1 month to

5 years, apparent oral clearance of valacyclovir in children less than 3 months of

age was 50 % than that in older children [119]

Adefovir OAT1, MRP4 Adefovir is partly renally cleared (45 %) [120, 121]. In 45 children (age range

2–17 years) receiving oral adefovir dipivoxil, weight-corrected mean apparent

clearance and renal clearance were higher in younger children [122]

ABC adenosine triphosphate (ATP)-binding cassette, AUC area under the plasma concentration–time curve, BCRP breast cancer resistance

protein, GFR glomerular filtration rate, HPT human oligopeptide transporter, IV intravenous, M3G morphine-3-glucuronide, MATE multidrug

and toxin extrusion protein, MPA mycophenolic acid, mRNA messenger RNA, MRP multidrug resistance-associated protein, OAT organic anion

transporter, OATP organic anion-transporting polypeptide, OCT organic cation transporter, PGx pharmacogenetics, PK pharmacokinetic, UGT

uridine 50-diphospho-glucuronosyltransferase


digoxin clearance to GFR ratio decreased by 45 %, sup-

porting intestinal and renal ABCB1-mediated inhibition

[39]. In contrast, the same drug–drug interaction resulted in

only a mild decrease in digoxin clearance in adults. These

findings support our hypothesis that renal clearance of

digoxin in young children may be more dependent on

ABCB1-mediated tubular secretion than in adults.

Interestingly, the hypothesis of higher renal ABCB1

expression after birth is supported by a mouse study

showing a relationship between renal Abcb1 expression

Fig. 2 Membrane transporters and their relationship with commonly

prescribed drugs to children: digoxin, tacrolimus, morphine, pravas-

tatin, and atorvastatin. ABC adenosine triphosphate (ATP)-binding

cassette, CYP cytochrome P450, OATP organic anion-transporting

polypeptide, OCT organic cation transporter, UGT uridine 50-diphos-

pho-glucuronosyltransferase


and digoxin clearance in young mice, but not by the limited

human data from neonates [21, 40].

3.2 Tacrolimus-ABCB1

The calcineurin inhibitor tacrolimus inhibits synthesis of

cytotoxic lymphocytes and so prevents transplant rejection.

Tacrolimus is a substrate for intestinal and hepatic ABCB1

(Fig. 2) [41]. Weight-normalized oral tacrolimus clearance,

which is also dependent on cytochrome P450 (CYP) 3A4/5

metabolism, is higher in infants between 1 and 6 years of

age than in older children and adults [42, 43]. CYP3A4

activity matures in the first year of life, while CYP3A5

activity, when present, appears stable from fetus to adult

[44].

Pharmacogenetic studies of ABCB1 in relation to

tacrolimus disposition appear contradictory [45]. In pedi-

atric heart and kidney transplant recipients no relation was

found between ABCB1 genotype and tacrolimus dosing

requirements or concentration/dose ratio [42, 43]. In

pediatric liver transplant patients, homozygous ABCB1

1236TT/2677TT/3435TT carriers needed higher tacrolimus

doses than non-carriers both early and later after trans-

plantation [42, 46]. In a population pharmacokinetic anal-

ysis in 114 pediatric liver transplant recipients, the ABCB1

2677G[T allele was associated with a higher pre-dose and

concentration/dose ratio at day 1 after transplantation [47].

Such associations were not found for recipient or donor

ABCB1 1199G[A and 3435C[T variants. These findings

can be understood from a combined ex vivo/population

pharmacokinetic study in 130 pediatric liver transplant

recipients. High intestinal ABCB1 mRNA expression was

associated with an almost twofold higher tacrolimus

clearance early after transplantation, indicative of a switch

from primarily intestinal to hepatic tacrolimus clearance

upon graft recovery [48].

The results from ex vivo studies suggesting

stable ABCB1 mRNA intestinal expression and lower

hepatic ABCB1 expression in young infants may explain

the pharmacogenetic findings and the impact of the recip-

ient intestinal ABCB1 on tacrolimus disposition [20, 22,

24, 48].

3.3 Daptomycin-ABCB1

The antibacterial daptomycin is used to treat infections

caused by Gram-positive bacteria including methicillin-

resistant Staphylococcus aureus (MRSA). Daptomycin is

excreted primarily by the kidney and is an ABCB1 sub-

strate. In 23 adult Caucasian patients, the ABCB1 3435T

single nucleotide polymorphism (SNP) was associated with

a higher intravenous daptomycin dose-normalized area

under the plasma concentration–time curve (AUC) and

lower steady state clearance [49, 50]. In 24 children (age

range 3–24 months), intravenous daptomycin clearance in

younger infants (approximately 20 mL/h/kg) was higher

than previously reported for older children and adults

(8–13 mL/h/kg) [51, 52]. Likewise, in 20 preterm and term

infants (32–40 weeks of gestational age and 0–85 days’

postnatal age, the mean clearance was approximately

20 mL/kg/h) [53]. No relationship with gestational or

postnatal age was found, possibly due to the small sample

size. The maturation pattern of daptomycin pharmacoki-

netics resembles that of digoxin pharmacokinetics, with

higher clearance values early in life. This pattern is not

consistent with immature GFR, but may reflect a com-

pensatory role of ABCB1-mediated renal tubular secretion

in young children. As discussed earlier, this may be the

result of increased renal ABCB1 expression in young

infants, but these findings need to be confirmed [16, 18,

21].

3.4 Fexofenadine-OATP2B1

The antihistamine fexofenadine is mainly excreted through

bile as parent drug. Only a minor part is metabolized by

intestinal microflora and CYP3A4. Its disposition appears

to be subject to membrane transport by the uptake trans-

porter OATP2B1, the efflux transporter ABCB1, and pos-

sibly ABCC2 [54–56]. In 14 healthy men, fexofenadine

clearance was related to OATP2B1 polymorphisms and

simultaneous apple juice ingestion [57]. This latter finding

of a potential food–drug interaction concerning OATP2B1

substrates may be even more relevant for children, as

heavy consumers of apple juice. In a population pharma-

cokinetic study in 515 Japanese children (6 months to

16 years), CL/F was stable across the age groups (1 L/h/

kg) with the exception of the 6- to 12-year-olds, whose

clearance was 1.5-fold higher (1.5 L/h/kg) [58]. In another

population pharmacokinetic study including 46 Caucasian

and 31 non-Caucasian children (6 months to 12 years) and

138 adults, apparent bodyweight-normalized oral clearance

was lower in children less than 1 year of age than in older

children and adults [59]. Interestingly when comparing

ethnicities, the CL/F was slightly higher in the 6- to

12-year-old Japanese children (1.5 L/kg/h) than in 14 non-

Japanese children (0.8 L/h/kg) (13 Caucasian and one non-

Caucasian), but this difference may be due to the small

sample size rather than ethnicity [58].

Ex vivo data in these age groups are lacking, but

OATP2B1 gene expression in 15 neonatal intestinal sam-

ples obtained during surgery was nearly three times higher

than in adult samples [22]. This may imply higher oral

absorption of fenofexadine in neonates and young infants.


3.5 Morphine-ABCB1 and OCT1

The opioid morphine is almost completely metabolized by

uridine 50-diphospho-glucuronosyltransferase (UGT) 2B7

and UGT1A1 to morphine-3-glucuronide and morphine-6-

glucuronide. The disposition of both morphine and/or its

metabolites is subject to membrane transport by the uptake

transporters organic cation transporter (OCT) 1 and

OATP1B1 and by the efflux transporters ABCB1, ABCC2,

and ABCC3 (Fig. 2) [60, 61]. Hepatic uptake of morphine

appeared to be OCT1-mediated in an adult volunteer study

and carriers of loss-of-function SLC22A1 gene polymor-

phisms showed higher morphine AUCs [61]. In other

healthy adult volunteers, co-administration of the ABCB1

inhibitor quinidine altered both morphine pharmacokinet-

ics and its opioid effects after oral but not after intravenous

morphine administration, suggesting a limited role for

ABCB1 in the disposition of morphine at the liver and

blood–brain barrier [62]. In adult cancer patients receiving

oral morphine, pain relief was more prominent in

homozygous carriers of the ABCB1 3435T/T SNP, proba-

bly due to higher intestinal uptake [63].

Age-related morphine clearance in neonates and infants

is very low in the first 10 days of life and increases

thereafter [64]. Although this pattern was explained by

UGT2B7 maturation, an impact of the maturation of the

relevant transporters cannot be ruled out. Interestingly, in

follow-up studies in which morphine doses were adjusted

to the age-related clearance and similar exposure was

reached across the first year of age, pain relief was ade-

quate in neonates (\10 days of age), but the older children

still needed high doses of rescue morphine [65]. Neonates

are more prone to respiratory depression, which may be

explained by increased exposure to morphine when doses

are not adjusted to the age-related changes in its disposi-

tion. In addition, immature ABCB1 activity at the blood–

brain barrier, as shown very recently, cannot be ruled out to

contribute as well and deserves further study [29].

Sadhasivam and co-workers [66, 67] have extensively

studied the impact of genetics of transporters in a large

cohort of infants and children receiving intravenous mor-

phine for tonsillectomy. In 220 infants, OCT1 homozygous

genotypes (SLC22A1 1365GAT[del/1498G[C) were

associated with lower morphine clearance and lower mor-

phine glucuronide formation [68]. ABCC3 homozygous –

211 CC carriers showed (approximately 40 %) higher

metabolite transformation, indicating increased efflux of

metabolites into plasma. ABCB1 polymorphisms (3435

C[T) only affected morphine-3-glucuronide formation, not

morphine or morphine-6-glucuronide pharmacokinetics. It

should be noted that only pharmacokinetic data up to

45 min post-dosing were available and, hence, the full

pharmacokinetic profile of morphine and its metabolites

could not be determined. In 263 children of the same

cohort, the ABCB1 G allele of the rs9282564 polymor-

phism was associated with respiratory depression, resulting

in prolonged hospital stay (odds ratio 4.7; 95 % confidence

interval 2.1–10.8, P = 0.0002) [66]. This study contrasts

with the adult study in which ABCB1 inhibition did not

influence the effect of morphine after intravenous admin-

istration [62]. In the extended cohort, now including 347

children, the interaction of genetic variants of ABCB1 and

two other genes, the fatty acid hydrolase (FAAH, which has

been associated with opioid use and addiction acting via

cannabinoid receptor type 1), and the b2-adrenergic

receptor (ADRB2, receptor blockade has been associated

with pain and pain relief), helped discriminate low and

high risk for morphine-related postoperative respiratory

depression [67].

As hepatic ABCB1 gene expression only appears to

reach adult levels after the first year of life [20, 22, 24, 48],

immature hepatic and possibly also blood–brain barrier

ABCB1 expression may play a role in higher morphine

plasma and brain exposure and the higher risk for respi-

ratory depression in neonates.

3.6 Pravastatin-OATP1B1

Clearance of the cholesterol synthesis inhibitor pravastatin

is mainly dependent on non-CYP450-mediated drug

metabolism and several uptake and efflux transporters,

such as OATP1B1, OATP2B1, OATP1B3, ABCB1, and

ABCC2 (Fig. 2) [69]. In adults, SLCO1B1, but not ABCC2,

ABCB1, or ABCG2, gene variants were associated with

inter-individual variability in pravastatin pharmacokinetics,

suggesting a major role of SLCO1B1 in pravastatin dis-

position [70, 71].

Intriguingly, in one small pharmacogenetic study

(n = 20; mean ± standard deviation age 10.3 ± 2.9 years),

children with familiar hypercholesterolemia with the

SLCO1B1 –11187GA genotype had lower mean pravastatin

AUCs than children with the wild type [72]. The opposite

effect was found in an adult study (n = 41) [71]. These

results, which should be interpreted with care in view of the

small sample size, suggest age-related post-translational

differences in OATP1B1 expression. The pharmacokinetics

of pravastatin in children (aged 5–16 years) were similar to

adults, which suggests no major impact of age-related vari-

ability in OATP1B1 or other transporter activity from

5 years onwards [73]. These results appear to be in line with

the ex vivo results of stable hepatic OATP1B1 expression in

older children [25].


3.7 Atorvastatin-OATP1B1

Another cholesterol synthesis inhibitor increasingly used in

children is atorvastatin. Like the other statins (HMG-CoA

reductase inhibitors), atorvastatin is extensively metabo-

lized, largely by CYP3A4, and is a substrate for OATP1B1

(hepatic uptake) and ABCG2 (oral absorption) (Fig. 2). In

a population pharmacokinetic study in pediatric hyperc-

holesterolemia patients aged 6–17 years, atorvastatin CL/

F was described as a function of bodyweight. When scaled

allometrically, CL/F was similar to values reported for

adults [74]. Atorvastatin metabolism is probably mature

from 6 years onwards. The stable clearance and the exist-

ing ex vivo data of OATP1B1 suggest similarly mature

transporter activity, although an age-related change in the

relative contribution of individual transporters cannot be

ruled out [25, 26]. We could not identify pediatric phar-

macogenetic atorvastatin studies, although a comprehen-

sive study in adults clearly indicated the SLCO1B1 variant

388A[G as a major determinant for atorvastatin pharma-

cokinetics [75].

3.8 Bosentan-OATP2B1

Bosentan is metabolized by CYP3A4 and CYP2C9, with

both the parent compound and one metabolite being phar-

macological active, but is also subject to hepatic uptake by

OATP1B1, OATP1B3, and maybe OATP2B1 [76]. Next to

the developmental pattern of CYP3A4, CYP2C9 already

shows an increase prenatally, with stable, though variable,

activity after the first week of postnatal age [77, 78]. Hence,

the impact of the maturation of the transporters may be

compounded by CYP3A4 and CYP2C9 maturation in the

first year of life, but age-related variation as observed later in

life may be more likely due to transporter maturation. At oral

doses of approximately 2 mg/kg, bosentan plasma exposures

for 19 children (aged 3–15 years) were similar to those for

healthy adults [79]. In children [n = 36, median (range) age

7.0 (2–11) years], plasma concentrations did not further

increase at doses higher than 2 mg/kg (exposure limit), while

in adults the exposure limit was 7 mg/kg, with no difference

in the other pharmacokinetic parameters [80]. As bosentan

appears to be an OATP2B1 substrate, intestinal saturation

due to immature OATP2B1, and perhaps other anatomical or

physiological age-related differences in oral absorption, may

explain this observation. This result does not correspond

with the OATP2B1 mRNA expression results, suggesting

higher expression in neonates than in adults [22]. In a pedi-

atric population pharmacokinetic–pharmacogenetic study

[n = 46, mean (range) age 3.8 years (25 days–16.9 years)],

no relationship between bosentan pharmacokinetics and

genetic polymorphisms of SLCO1B1, SLCO1B3, SLCO2B1,

or CYP3A5 was found [81].

3.9 Ondansetron-OCT1

The anti-emetic ondansetron is mainly metabolized by

CYP2D6, which contributes to genetic variation in its

disposition and effect. In addition to this CYP2D6 effect,

the pharmacokinetics (n = 45) and clinical efficacy

(n = 222) of ondansetron in adults (age range

18–83 years) have also been correlated with SLC22A1

genotypes [82]. OCT1 deficiency potentially limits the

hepatic uptake and increases plasma concentrations of

ondansetron [82]. In a population pharmacokinetic analysis

of 124 patients in the age range 1–48 months, ondansetron

bodyweight-normalized clearance was reduced by 76 % in

a 1-month-old patient and by 31 % in a 6-month-old

patient, compared with the older children [83]. This con-

trasts with evidence from both in vitro and in vivo studies

suggesting maturity of CYP2D6 activity as early as

1–12 weeks postnatal [84–86]. Thus, we hypothesize that

lower ondansetron clearance in the first year of life may be

related to immature OCT1 activity.

3.10 Metformin-OCT1 and MATE1

Several transporters have been implicated in metformin

elimination, tissue distribution, and response. OCT1 is a

major determinant of the hepatic uptake of metformin,

while multidrug and toxin extrusion protein (MATE) 1/

MATE2-K determine the efflux of metformin [7, 34].

Recently, the transcription factor hepatocyte nuclear factor

1 was found to regulate OCT1 expression and was related

to metformin pharmacokinetics and pharmacodynamics

[87, 88]. The combination of SLC22A1 (OCT1) and

SLC47A1 (MATE1) genotypes further explains variation in

response to metformin in adults [8, 89]. In contrast, in 140

non-obese adolescent girls with androgen excess after

precocious pubarche, SLC22A1 genotype was not related to

metabolic response at 1 year of metformin treatment [90].

In non-obese 9-year-old girls and diabetic patients aged

12–16 years, pharmacokinetics were comparable with

those in adults [91, 92]. This suggests stable OCT1 or

MATE activity from the age of 9 years onwards, but this

needs further study, especially since data in younger chil-

dren are lacking.

3.11 Cimetidine-OCT2

In adults, renal excretion of the histamine H2-receptor

antagonist cimetidine and its metabolites accounts for

60 % of total clearance, versus 80–90 % in children and

neonates [93–95]. Cimetidine is partially metabolized and

is a substrate of the uptake transporters OCT2 and organic

anion transporter (OAT) 2 and the efflux transporters

MATE1 and MATE2-K [8, 34, 96, 97]. Cimetidine is a


well-known OCT2 inhibitor and therefore could potentially

counteract OCT2-driven cisplatin oto- and renal toxicity

[98]. Although the drug is now rarely used in pediatric

clinical care, this latter promise necessitates a full under-

standing of its disposition across the pediatric age range, as

part of studies to confirm this new indication. The rela-

tively high renal clearance in neonates and children sug-

gests an important role for renal tubular secretion and

suggests mature activity already at birth. On the other hand,

Ziemniak et al. [94] suggest that the unexplained gap

between total and renal clearance in adults could be due to

secondary metabolite formation in adults, which maybe

missing in neonates due to immature metabolism. This is

less likely, however, as the higher renal clearance was also

observed in older children, whose drug metabolism is lar-

gely at adult levels. Moreover, in a rat study, bile duct

ligation increased cimetidine renal tubular secretion by up-

regulation of OCT2 (but not MATE1), supporting the

hypothesis that the non-renal clearance in adults occurs

through hepatic/bile excretion and is not related to

unknown secondary metabolite formation [99]. Neverthe-

less, as analytical methods to measure drugs and metabo-

lites have become more sensitive since the early studies in

the mid-1980s, new studies in children of different ages

could help elucidate why renal clearance of cimetidine

differs between children and adults and give insight into

the role of OCT2 in cimetidine disposition.

3.12 Tramadol-OCT1

Tramadol is a prodrug of the l-opioid receptor agonist O-

desmethyltramadol. It is metabolized mainly by CYP2D6

to its active O-desmethyltramadol metabolite [100]. The

variation in tramadol pharmacokinetics cannot solely be

explained by variation in CYP2D6, as was shown by

Tzvetkov et al. [101] who showed an additive effect of

OCT1 on tramadol disposition variation. Loss-of-function

SLC22A1 polymorphisms have been related to higher

plasma concentrations of the active O-desmethyltramadol

and prolonged miosis, as a surrogate marker of the opioid

effect. These effects are likely due to reduced OCT1-me-

diated hepatic uptake [101]. Allegaert and co-workers

[102] showed that maturational clearance of tramadol,

driven by CYP2D6 activity, is almost complete by

44 weeks post-menstrual age. In a pooled population

pharmacogenetics–pharmacokinetic study covering the age

range from preterm to elderly, only part of the variability in

O-desmethyltramadol formation clearance could be

explained by the CYP2D6 genotype, further supporting a

potential role for SLC22A1 genetic variation [86]. A rela-

tionship between CYP2D6 genotype and tramadol meta-

bolism was shown in young preterm infants, which is

surprising as CYP2D6 is not fully mature at birth,

especially not in preterm infants, and a genotype effect

may have been obscured. It would be worthwhile, there-

fore, to study the impact of the SLC22A1 genotype in this

young population [10]. In a population pharmacokinetic/

pharmacodynamic analysis of 104 older children

(2–8 years), age did not clearly contribute to variation in

pharmacokinetics or the prediction of response [103].

3.13 Methotrexate-OATP1B1 and ABCC2

Methotrexate is a folic acid antagonist used to treat several

forms of cancer and anti-inflammatory diseases.

Methotrexate undergoes complex hepatic and intracellular

metabolism [104]. Many membrane transporters are

responsible for its uptake and excretion and for its meta-

bolism to active polyglutamine metabolites and inactive

7-hydroxy-methotrexate [104, 105]. Methotrexate is elim-

inated primarily by renal excretion through glomerular

filtration and renal tubular reabsorption and secretion.

Approximately 70–90 % of a dose is excreted unchanged

in urine. A small pharmacokinetic study showed only

marginally lower methotrexate steady-state clearance

(body surface area corrected), but increased renal toxicity,

in 0- to 3-month-old infants than in 7- to 12-month-old

infants [106, 107]. From 1 year of age onwards,

methotrexate clearance (body surface area normalized)

decreased linearly with age [107]. A 2014 review con-

cluded that ‘‘although there is no pharmacogenetic marker

for MTX [methotrexate] in use in the clinic at present,

polymorphisms in SLCO1B1 have an important role in

MTX pharmacokinetics and toxicity in pediatric ALL

[acute lymphoblastic leukemia] patients and show the most

consistent and promising results’’ [105]. For example, in a

cohort of almost 500 pediatric acute lymphoblastic leuke-

mia (ALL) patients, the methotrexate AUC from time zero

to 48 h (AUC48) increased by 26 % (P\ 0.001) per

SLCO1B1 rs4149056 C allele and was a significant pre-

dictor of overall toxic adverse events during methotrexate

courses (R2 = 0.043; P\ 0.001), but no relationship was

found for ABCC2 [107]. This study confirmed the results of

a genome-wide association study (GWAS) in 434 ALL

children, the first to identify SCLO1B1 genetic variation as

an important marker of methotrexate pharmacokinetics and

clinical response, and was recently validated by five dif-

ferent treatment regimens of high-dose methotrexate in

ALL treatment protocols at St Jude Children’s Research

Hospital (Memphis, TN, USA) [108]. Moreover, a deep

sequencing approach for SLCO1B1 demonstrated that rare

damaging variants contributed significantly to methotrex-

ate clearance and had larger effect sizes than common

SLCO1B1 variants [109, 110]. Other recent studies have

detected a relationship between ABCC2 and methotrexate

pharmacokinetics and toxicity. In 112 Han Chinese


pediatric ALL patients, the ABCC2 –24T allele (rs717620)

was associated with significantly higher methotrexate

plasma concentrations at 48 h and with significant hema-

tological and non-hematological toxicities. These findings

are partially supported by other studies in 127 Lebanese

and 151 Spanish pediatric ALL patients [111, 112].

3.14 Mycophenolate Mofetil-ABCC2

Mycophenolate mofetil is the prodrug of the active

mycophenolic acid (MPA). It is metabolized by car-

boxylesterase 2 (CES2), after which MPA is further

metabolized by several CYPs and UGTs [113]. MPA-glu-

curonide is excreted in the bile primarily by ABCC2 (en-

coded by ABCC2) and this transport is essential for

enterohepatic circulation. The ABCC2 rs717620 A allele

has been associated with reduced exposure to MPA in

pediatric renal transplant recipients [114]. In a large mul-

ticenter cohort of pediatric heart transplant recipients,

ABCC2 rs717620 A allele was also associated with more

gastrointestinal intolerance, but with fewer short- and long-

term rejection episodes [114]. As ABCC2 is thought to

excrete MPA-glucuronide in the bile, carriers of the active

A allele, may have increased enterohepatic circulation with

an increased concentration of free MPA in the intestine.

This is potentially associated with more gastrointestinal

intolerance, but simultaneously with higher exposure and

efficacy. As SNPs in UGT1A9, UGT2B7, SLCO1B3, and

IMPDH have also been associated with altered MPA

exposure, the combined effect of these SNPs and poten-

tially interacting co-medication, may define high- and low-

risk patients for MPA efficacy and toxicity. Full hepatic

ABCC2 maturation appears to occur after infancy, sug-

gesting a lower enterohepatic circulation of MPA, which

may result in less gastrointestinal intolerance but poten-

tially also with less efficacy in this age group [22]. This is

merely a hypothesis without confirming pharmacokinetic

data.

3.15 Acyclovir/Valacyclovir-OAT1 and OAT3

The oral bioavailability of the anti-viral agent acyclovir is

poor, and therefore its prodrug valacyclovir was developed.

A positive association was found between intestinal

expression of 4F2hc (SLC3A2, amino acid transporter

heavy chain, a membrane glycoprotein), and HPT1 (human

oligopeptide transporter) and plasma levels of valacyclovir,

but not peptide transporter 1 [PEPT1 (SLC15A1)] or any of

the other investigated intestinal organic anion or cation

transporters [115].

After hepatic metabolism, both drugs are mainly renally

excreted by both glomerular filtration and renal tubular

secretion, most likely by OAT1 and OAT3 [116, 117]. In

preterm and term neonates (n = 28, median age 30 weeks

of gestation), the intravenous acyclovir bodyweight-cor-

rected clearance showed a twofold increase from 25 to

41 weeks of gestational age [118]. In children 1 month to

5 years old with or at risk for herpes infection, the CL/F of

valacyclovir (mL/kg/min) in those younger than 3 months

was 50 % of that in older children, in whom bodyweight-

corrected clearance remained stable [119]. A recent study

showed markedly increased acyclovir concentrations when

co-administered with benzylpenicillin, which was shown to

be due to OAT3 and possibly OAT1 inhibition [116]. This

could be a very relevant interaction in septic newborns,

who often receive both drugs, as increased acyclovir con-

centrations are associated with neurological adverse events

as well as neutropenia.

3.16 Adefovir-OAT1 and ABCC4

Adefovir, the antiviral agent used for treatment of hepati-

tis B virus or HIV, is 45 % renally cleared through

glomerular filtration and OAT1/ABCC4 renal tubular

secretion [120, 121]. In 45 children in three age groups

(2–6, 7–11, and 12–17 years) receiving oral treatment for

hepatitis B virus with the prodrug adefovir dipivoxil,

bodyweight-corrected mean apparent clearance and renal

clearance were decreasing with increasing age [122].

Similarly, in a phase I study in children (n = 13, age range

6 months to 18 years) receiving oral adefovir dipivoxil for

HIV treatment, systemic exposure was lower in children

younger than 5 years [123].

4 Summary and Discussion

In summary, ex vivo, pharmacokinetic and pharmacogenetic

studies suggest transporter-specific changes from the human

fetus to the adult. At this time, data are very scarce and the

impact of these changes on drug therapy in children is still

largely unknown. However, despite data scarcity, our review

may aid clinical pharmacologists and clinicians in rationale

drug prescribing of the drugs presented, not only by showing

how pharmacokinetics are probably similar in certain pedi-

atric age groups compared to adults, but also by pointing out

where potential age-related changes in individual trans-

porters could impact the drug’s efficacy and safety. It

broadens our views on ontogeny of transporters by evalua-

tion of the results of pharmacokinetic and pharmacogenetic

studies on relevant transporters. Moreover, this review pre-

sents clear information gaps, which may guide future

research efforts to elucidate the role of human membrane

transporters in the developing child.

For most drugs, the in vivo data to support the ex vivo

data in understanding the maturation of individual


transporters are limited to older children, and, hence, their

usefulness is limited. No clear transporter maturation pat-

tern can be deducted from any of the available pharma-

cokinetic studies in children. This contrasts with our

knowledge from individual DMEs. For example, using

midazolam as a phenotyping probe, the developmental

expression of CYP3A4/5 from the preterm neonate to the

adult has been extensively characterized [124, 125] as has

amikacin clearance to display the maturation of GFR in

neonates [125]. Specific phenotyping probes to study

individual membrane transporters are suboptimal and have

only been validated in adults. For many drugs, multiple

transporters are involved in their uptake and excretion,

which in turn may also compensate for changes in indi-

vidual transporter activity. In adults, knowledge has also

been gained from pharmacogenetic and drug–drug inter-

action studies.

This review shows that pharmacogenetic variation in

membrane transporter activity also impact drug disposition,

effect, and toxicity in children. Most pharmacogenetic

studies in children are in line with adult data. However,

these similar pharmacogenetic relationships should be

interpreted with care, especially when it comes to trans-

lating these data across the whole pediatric age range. First,

most pharmacogenetic study cohorts only contain older

children, whereas pharmacokinetic studies in neonates and

infants often show clear developmental changes up to

4–6 years of age. Hence, the impact of SNPs may be

obscured by more prominent changes due to growth and

development. Second, the relationship between SLCO1B1

SNPs and pravastatin disposition in adolescents was found

to be the opposite of that in adults. If these results are

validated in other studies, a potential impact of hormonal

changes on individual transporters needs to be elucidated;

this may also provide insight into the physiological role

these transporters play during adolescence.

The limited data from ex vivo studies of postmortem or

surgical samples support the notion of membrane trans-

porter-specific maturational patterns. It is still difficult,

however, to determine definitive patterns for the different

transporters. One of the reasons for this is that most studies

only used limited samples and limited age ranges. Most

fetal and neonatal studies only applied immunohisto-

chemistry or mRNA techniques, while the more quantita-

tive protein expression data are mainly from older children,

above the age range in which most developmental changes

can be expected. In addition, the quality and interpretation

is further challenged as the exact origin, handling, and

storage of tissues, including detailed patient characteristics

and exact procurement site from organ (e.g., where in the

intestine?), is often unknown.

The mechanisms underlying maturational changes in

transporters are largely unknown. Recent studies on

CYP3A4 show maturational changes in methylation pat-

terns to mirror the maturational expression of CYP3A4,

which may point towards similar mechanisms for the

transporters [126].

Differences between ethnic groups in DME abundance

or ethnicity have been described, even in newborn infants

[77, 85, 127]. Like in DMEs, it is credible to believe that

ethnicity might have an effect on transporter activity or

abundance. Nevertheless, for 27 drug transporters in 95

pathologically normal kidney samples, the expression did

not differ between European Americans or African

Americans [128].

The interpretation of pharmacokinetic studies, to

understand maturation of transporters, is complicated by

the fact that these transporters are part of the larger system

of the ADME processes involved in the disposition of

drugs. In contrast to DMEs, where clearance to a specific

metabolite can be estimated to understand the DME mat-

uration, studying a single transporter is more difficult. One

may not be able to pinpoint one specific membrane trans-

porter involved, and if the dominant transporter is still

immature early in life, other transporters may compensate,

thereby obscuring individual transporter maturation.

5 Future Directions

Several approaches are needed to increase our under-

standing of membrane transporters in the fetus and child

(Table 3). First, the impact of transporter maturation on

efficacy and toxicity in daily clinical care needs to be

elucidated. Pharmacogenetic studies can be a powerful tool

to this aim, provided they have adequate power and vali-

dation cohorts, the lack of which is a major limitation of

currently published studies. Studies need to not only be

powered to study the impact of a single SNP in one

transporter gene, but at the least, the interaction with age

should be part of their designs. Preferably such studies

should be designed to study the disposition of a drug in the

context of systems pharmacology, also including SNPs in

other relevant pharmacokinetic and/or pharmacodynamic

genes, as well as pharmacokinetic sampling enabling the

separation of different excretion pathways (e.g., GFR vs.

tubular secretion vs. bile secretion vs. metabolism). In

addition to pharmacogenetic studies, well-designed studies

reflecting clinical drug–drug interaction scenarios may

improve our understanding of transporter maturation, such

as pharmacokinetic studies in which patients’ samples are

taken before/during/after co-medication with a potentially

interacting drug. For example, the carvedilol–digoxin study

[39] or the older cimetidine studies in neonates in which

renal clearance by glomerular filtration could be separated

from renal tubular secretion [94], have, by their design,


provided support for age-related differences in specific

renal transporters.

Ethical challenges have limited studies in infants and

neonates. However, many drugs in our review are regularly

prescribed, even for these young children. Therefore,

opportunistic sampling or biobanking of left-over samples

from children who take these drugs for therapeutic reasons

may aid overcoming these ethical barriers.

At this time, endogenous markers to phenotype the

activity of individual transporters are lacking. With the

increased availability of metabolomics, specific metabo-

lites or metabolite ratios may be identified to reflect

transporter activity in vivo. A recent GWAS–metabolomics

study detected specific metabolites/metabolite ratios for

selected transporters such as OCT1 [129–133]. The feasi-

bility of this approach was recently shown for CY2D6

phenotyping in children [129]. To design drug-dosing

regimens in children, population PBPK models are

increasingly being used [134]. Modeling and simulation

can be used in different ways to increase our understanding

and to design dosing regimens. Using a systems approach,

modeling of the disposition of a substrate model drug can

result in a mathematical description of the maturation of

the specific transporter. This maturational description can

then be used to simulate dosing guidelines for other

transporter substrates. The feasibility of this approach has

been used to describe maturation of selected DMEs and

GFR clearance [133, 135]. Secondly, PBPK modeling,

which incorporates available drug property and physio-

logical information, could be used to simulate the impact of

maturation of specific transporters, preferably with actual

ex vivo data on transporter expression/activity [134]. An

example is a mechanistic PBPK model to predict morphine

levels in breast-fed neonates of codeine-treated mothers

[136]. A major limitation of these models is the lack of

high quality ex vivo data on transporter activity across the

pediatric age range and the lack of in vivo validation of

these models.

In the design of new studies, the following issues should

be considered. The collection of these data can only be

achieved by an international effort to collect high-quality

tissue in collaboration with surgeons, pathologists, ethi-

cists, clinical researchers, and experts in drug transporter

research. The limitations of current tissue collections have

been described here and good protocols for tissue collec-

tion, preferably in the context of internationally accessible

biobanks, should be developed. Newer laboratory tech-

niques should be strongly considered to minimize tissue

amounts needed, for example, for laser capture and LC–

MS/MS to determine protein abundance. Moreover, a

multi-omics approach, including not only genomics but

also transcriptomics, proteomics, metabolomics, and

microbiomics, may provide greater power to predict drug

efficacy and adverse drug reactions [137, 138]. Also, with

the fast developments in tissue engineering, the current

ethical and practical issues regarding tissue sampling and

storage could be overcome using pediatric-engineered tis-

sues. This may even enable transporter activity studies,

which are now not available in pediatric tissue.

Acknowledgments We would like to thank J. Hagoort for editorial

assistance.

Compliance with Ethical Standards

This work was supported in part by the Netherlands Organisation for

Health Research and Development (ZonMW SNW Clinical Fellow-

ship, grant 90700304), the German Federal Ministry of Education and

Research (Virtual Liver Network grant 2318 0315755), the Robert

Bosch Stiftung, Stuttgart, Germany, and the ICEPHA (Interfacultary

Centre for Pharmacogenomics and Pharma Research) Graduate

School Tubingen-Stuttgart, Germany. MGM, ATN, CAJK, ES, DT,

MS and SNW have no conflict of interest.

Open Access This article is distributed under the terms of the

Creative Commons Attribution-NonCommercial 4.0 International

License (http://creativecommons.org/licenses/by-nc/4.0/), which per-

mits any noncommercial use, distribution, and reproduction in any

medium, provided you give appropriate credit to the original

Table 3 Approaches to future transporter studies

Ex vivo research

Build multidisciplinary research teams for tissue collection and

study design, e.g., surgeons, pathologists, clinical study staff,

basic researchers

Use optimal age distribution, e.g., tissues samples from fetuses,

neonates, and young infants, where most developmental changes

can be expected, as well as sample number to ensure adequate

power to detect age-related changes

Establish high-quality tissue collections with detailed tissue

handling description and detailed description of patient

characteristics

Use protein quantification techniques (e.g., LC–MS) and develop

tools to study activity with minimal amounts of human tissue

PK studies

Phenotyping studies with drugs that are clinically used, and

consider microdosing studies

Blood sampling at similar times as clinical blood draws

(opportunistic sampling)

Perform population PK analyses

Design drug–drug interaction studies

PGx studies

In pediatric populations, test genetic variants in transporters

known to affect PKs or PDs in adults

Take into account PGx variation in affected drug-metabolizing

enzymes as added variants

Include relevant age range: e.g., younger children and neonates

Design adequately powered studies

LC–MS liquid chromatography–mass spectrometry, PD pharmaco-

dynamic, PGx pharmacogenetic, PK pharmacokinetic


author(s) and the source, provide a link to the Creative Commons

license, and indicate if changes were made.

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